Diammonium salts



Patented Nov. 17, 1953 TDIAMMONIUM SALTS Franz .HifligerfBasl, and Emilems, Riehen, near Basel, Switzerland, assignors to J. R. GeigyA.G.,Basel, Switzerland, a Swissfirm 4N0 Drawing. Application-June 30, 1952,Serial No. 296,484

Claims priority, application Switzerland July 11, 1951 '2 Claims. (Cl.266-45675) This invention concerns 'new'diquaternary diammonium salts ofthe general formula:

Ph represents a member selected from the group consisting of the'ortho-phenylene and .paraphenylene radicals,

X represents a member selected from the group consisting of oxygen andsulphur,

n represents an integer from2 to 3,

R represents a lower aliphatic hydrocarbonvradical, and

An 9 represents a member selected from the group consisting ofhydrochloric, hydrobromic, hydroiodic, methylsulphuric and ethylsulphuric acid anions.

It has been found that these new salts have an interestingpharmacological action on the tonus of the muscles. Thus, for example,240 of the dimetho-iodide of 1-'( -dimethylaminopropoxy) 4 (vdimethylamino propylmercapto)-benzene obtained according to .Example 1has the same contracting-inhibiting or reducing eifect en the isolatedrat diaphra m accordingto Buelbring-Trevan as 100 of d-tubocurarine.

In contrast to this excellent action,.in comparative trials analogouscompounds such as for example the dimethoiodlde of l-(c-diinethylaminoethoxy) 4 (5 dimethylamino ethylmercapto)-benzene in which the two sidechains are in the meta-position to each other, have practically noeffect.

The diammonium compounds defined can be produced by reacting compoundsof the general formula:

SE at or salts thereof with two molecules of tertiary aminoalkyl halidesof'the general formulae:

and Ph, X,'R and n have the meanings given above and then treating theditertiary diamines with two molecules of low molecular alkylating agentor just with methylating agents.

Monothioand dithio-brenzcatechin and monothioand dithio-hydroquinone arethe starting materials of the general formula:

yen :Pn

They can be reacted as such or in the form of their salts with,B-dimethylamino-ethylor v-dimethylamino-propyi chloride, -bromide, or-io'- dide to form the following bis-dimethylaminoalkyl compounds:

1 (B dimethylamino ethoxy) 2 (B dimethylamino-ethylmercapto) -benzene,

1 ('y dimethylamino propoxy) 2 (v dimethylamino-propylmercapto)-benzene,

1.2 bis (B dimethylamino ethylmercapto)- benzene,

1.2 bis ('y dimethylarnino propylmercapto) benzene,

1 (fl dimethylamino ethoxy) 4 ([3 dimethylamino-ethylmercapto) -benzene,

1 ('y s dimethylamino propoxy) 4 ('y dimethylamino-propy1mercapto-benzene,

1.4 bis (5 dimethylamino ethylmercapto) benzene,

1.4 bis ('y dimethylamino-propylmercapto) benzene.

The following, e. g. are corresponding bisalkylmethylamino-alkylcompounds:

1 (B ethylmethylamino ethoxy) 2 (cethylmethylamino-ethy1mercapto)-benzene,

1 (c butylmethylamino ethoxy) 4 (flbutylmethylamino ethylmercapto)benzene, and

1 (v propylmethylamino propoxy) 4 ypropylmethylamino-propylrnercapto)-benzene.

These ditertiary diamines are suitable, for example, as startingmaterials for the direct production of dimethosulphates of diquaternarycompounds wherein B does not represent methyl radicals.

If the thiophenols are not converted before the reaction into salts bymeans of bases, then it is advantageous to perform the reaction in thepresence of a solvent and a base which binds the hydrohalic acid whichsplits oflf. Suitable bases are e. g. sodium amide, lithium amide sodiumhydride, sodium methylate, sodium hydroxide and potassium hydroxide. Ifalkali amides are used, neutral solvents and those having no hydroxylgroups such as diethyl ether, dibutyl ether, dioXan, benzene, toluene,xylenes and narafiin hydrocarbons are suitable, in addition alcoholssuch as ethanol or butanol are suitable if alcoholates are used and, ifalkali hydroxides are used, water is also suitable. The reaction isperformed at moderate temperatures, between 150.

The following compounds for example come into question asmethylatingagents and further alkylating agents by means of which theditertiary diamino compounds can be converted into diammonium compounds:methyl chloride, methyl bromide, methyl iodide, dimethyl sulphate, ethylchloride, ethyl bromide, ethyl iodide, diethyl sulphate, propyl bromide,propyl iodide, butyl and isobutyl bromide and iodide, amyl and isoamylbromide and iodide as well as allyl bromide and allyl iodide. Ifnecesary the reaction is performed in a closed vessel in the presence orabsence of solvents.

As the pharmacological activity of the diquaternary diarnrnoniurn saltsaccording to this invention depends chiefly on the cation, the type ofanion used in this invention is of lesser importance. The choice of theanion is determined, therefore, not only by pharmacological but also byvarious other factors such as accessibility of the alkylating agent,facility of reaction, crystallisability (possibility of purification)and water solubility of the products, so that from case to case, themost suitable solution can easily be found by a few trials.

In the quaternary ammonium salts particularly described in the followingexamples, the anion is an iodine ion. Apart from direct addition of thealkylating agent, salts with other anions can also be produced from thequaternary salts obtained by direct addition by double reactionaccording to methods fillOWll per se or by reacting the ammonium basewith a hydrohalic or allsyl sulphuric acid.

Ihe greater part of the diquaternary ammonium salts are compounds whichform almost colourless crystals. To crystallise, particularly organicsolvents or suitable mixtures of such and possibly with water aresuitable, e. g. mixtures of agents having good solvent properties suchas alcohols or water with those having not so good solvent propertiessuch as acetone. The new salts dissolve in water with an almost neutralreaction.

The following examples serve to further illustrate the production of thenew salts. Where not otherwise stated, parts are always given as partsby weight in grammes and their relationship to parts by volume is thatof grammes to cubic centimetres. ihe temperatures are in degreescentigrade.

Example 1 12.6 parts of monothiohydroquinone, 30.0 parts of-dimethylamino propyl chloride and 160 parts by volume of abs. tolueneare heated to ill-50 in a pure nitrogen atmosphere and then a suspensionof 11.3 parts of finely ground sodium amide in toluene is slowly addedin small portions while stirring. The whole is then stirred for 2 hoursat 40-5d and then boiled under reflux for 4 hours. After cooling,sufiicient 2 N hydrochloric acid is added while stirring to keep theaqueous layer acid to Congo red, the toluene layer is separated andwashed with a little water. The united hydrochloric acid and aqueoussolution is washed with ether, clarified by filtration (possibly with alittle animal charcoal) and then made strongly alkaline to mimosa with30% caustic soda lye. The base which precipitates is taken up in etherby shaking out twice. After drying the ether solution with potassiumcarbonate and distilling oii all volatile parts (finally at -100 under0.1 mm. pressure), l-( -dimethylaminopropoxy) ldimethylaminoproylmercapto)-benzene is obtained as an oil which can beclarified and made somewhat lighter in colour if necessary by filtrationwith charcoal or other similar agents.

2.96 parts of this base are dissolved in 1 3 parts by volume of abs.methanol and 2 parts by volume of methyl iodide are added. The reactionwhich takes place is moderated by gentle cooling in ice water. Thereaction product is then allowed to stand for 14 hours at about 30 afterwhich time dry ethyl acetate is carefully added so long as the solutionremains clear. A sample can easily be made to crystallise by theaddition of acetone, rubbing with a glass rod and cooling. A fewcrystals are added to the solution which is cooled to about 5. Afterallowing to stand for several hours, the liquid is drawn oil undersuction, the crystals are washed with dry acetone and dried at 40-50 inthe vacuum. The dimetho-iodide of 1-( -dirnethylamino-propoxy) 4 ('ydimethylamino propylmercapto) benzene melts at about 220 ondecomposition.

Example 2 A sodium methylate solution prepared from 5.5 parts of sodiumwith as little abs. methanol as possible is added to 15 parts ofmonothiobenzcatechin and 590 parts by volume of abs. toluene in anitrogenous atmosphere. The methanol is distilled off over a column,then 26 parts of dimethylaminoethyl chloride in parts by volume of abs.toluene are added dropwise to the mixture which is boiling under refluxand the whole is boiled for some hours. The mixture is cooled andl-(s-dimethylaminoethoxy) -2- (c-dimethylamino-ethylmercapto) -benzeneis isolated as described in Example 1.

8 parts of this base are dissolved in Si) parts by volume of acetone, 13parts of methyl iodide are added while gently cooling and finally thewhole is boiled under reflux for some hours. After cooling, thedimetho-iodide of l-(c-dimethylaminoethoxy) 2 (/3dimethylaminoethylmercapto) -benzene is drawn off under suction and iscrystallised, if desired from alcohol with the addition of a littlewater. M. P. about 278-28Q on decomposition.

The dietho-iodide of l-(fi-diznethylaminoethoxy) 2 (c dimethylaminoethylmer capto)-benzene which is produced in an analogous manner meltsat about 188.

Also 1 (/3 dimethylamino ethoxy) a (,8 dimethylamino ethylmercapto)benzene for example can be produced according to the processes describedin Examples 1 and 2. Its dimethoiodide melts at about 273 ondecomposition, the dietho-iodide melts at about 233-236.

ihe dimetho iodide or" lxl bis ('y di methylamino propylmercapto)benzene melts at 268 on decomposition.

Also the dimetho-iodides and dietho-iodides of l ('y dimethylaminopropoxy) 2 dimethylamino propylmeroapto) benzene, 1.2 his (cdimethylamino ethylmercapto) benzene, 1.2 bis ('y dimethylamino propylmercapto) benzene and 1.4 bis (o di methylamino ethylmercapto)benzene can be produced in an analogous manner.

5 Further, the dimethochlorides, dimethobromides, dimethosulphates,diethochlorides, di-

ethobromides, diethosulphates, dipropobromides;

dipropo-iodides, dibutobromides, dibuto-iodides, di-isobutobromides,di-isobuto-iodides, diamyloiodides, diallylobromides anddiallylo-iodides of the above mentioned ditertiary diamino compounds andalso of 1 (B dimethylamino ethoxy) 2 (,3 dimethylamino ethylmer capto)benzene, 1 (p dimethylamino ethoxy) 4 (,3 dimethylamino ethylmer capto)benzene, 1 (v dimethylamino propoxy) 4 ('y dimethylaminopropylmer capto)benzene and 1.4 bis (v dimeth ylamino propylmercapto) benzene can beproduced in the same way.

What we claim is:

1. A diquaternary diammonium salt of the general formula:

wherein Ph represents a member selected from the group consisting of theortho-phenylene and paraphenylene radical,

X represents a member selected from the group consisting of oxygen andsulphur,

n represents an integer from 2 to 3,

R stands for lower alkyl, and

Anrepresents a member selected from the group consisting ofhydrochloric, hydrobromio, hydroiodic, methyl sulphuric and ethylsulphuric acid anions.

2. The dimetho iodide of 1 ('y dimethyl amino propoxy) ('y dimethylaminopropylmercapto) benzene of the formula:

FRANZ HAFLIGER. EMIL GIROD.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,087,131 Taub et a1. July 13, 1937 2,544,076 Fourneau Mar. 6,1951

2. THE DIMETHO - IODIDE OF 1 - (U - DIMETHYLAMINO - PROPOXY) - 4 - (Y -DIMETHYLAMINO PROPYLMERCAPTO) - BENZENE OF THE FORMULA: